(S)-6-methoxy-.alpha.-methyl-2-naphtaleneacetic acid (naproxen) is a long-known non-steroid anti-inflammatory drug, which also has analgesic and antipyretic activity (U.S. Pat. Nos. 3,904,682 and 4,009,197).
Because of the anti-inflammatory and analgesic activities of naproxen, it is indicated for treating various forms of arthritis, such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and gout arthropathy; as well as for treating forms of extraarticular rheumatism, such as lumbar sciatica, myalgia, neuralgia, radicular syndromes, periarthritis, myofibrositis and the like.
Therapy generally involves the use of daily doses ranging from 250 mg to 1,000 mg of active ingredient and the formulations currently available for administration include tablets, capsules, granules for extempore suspension (oral route), suppositories (rectal route), vials (intramuscular route), gels and emulsions (topical route). All these formulations are essentially designed to make the active ingredient readily available in the body in order to ensure a rapid onset of the therapeutic effect.
In particular, with respect to the oral administration route, the wish to extend the duration of the therapeutic effect led to the development of controlled drug release formulations to enable a single daily administration. It is in fact known that once-daily administration enables better patient compliance with recommended dosages during therapeutic treatment. For instance, patient compliance is reported to vary from 87% for drugs taken once a day to 39% for drugs taken four times a day (J. A. Cramer et al., JAMA It. ed. 1, 601 (1989)).
Examples of formulations suitable for once-daily administration are reported in U.S. Pat. No. 4,803,079, which describes the use of a matrix in which the active ingredient is dispersed and released by diffusion, as well as in European Patent Application EP 458,249 which describes the use of slow release pellets for the administration of a delayed release dose together with a ready release dose; and in European Patent EP 250,374, which describes solid dosing units suitable for the controlled release of drugs, including naproxen, with zero order kinetics.
The main drawback of all of these applications is the final large size and high weight of the solid dosage unit. This is particularly true of dosages with a high active ingredient content (as is the case with naproxen). Thus, for instance, by applying the teachings of patent U.S. Pat. No. 4,803,079, a tablet containing 1,000 mg of active ingredient would have an overall weight of about 1,300 mg, a diameter of about 15 mm, and a thickness of about 7 mm.
Obviously, administration of a dosage unit with these dimensions and weight to patients with difficulty swallowing presents a problem. This is not a minor problem considering that, for the above types of diseases, the patient population that uses naproxen is generally made up of elderly individuals.
Even when the formulation is broken down into micro-units (granules or pellets), the need to avoid overdosing (which in the case of naproxen may induce torpor, heartburn, dyspepsia, nausea or vomiting) requires that the micro-units be enveloped in a container (e.g. a gelatine capsule). The container will have dimensions similar to the ones above, and, therefore, will not avoid swallowing problems.
A further disadvantage of the oral administration of solid controlled-release dosage forms in the case of naproxen is that the active ingredient carried either in a tablet or in a capsule may cause local gastrointestinal contact intolerance which may occasionally cause bleeding in the gastrointestinal tract, peptic ulcer or colitis.
The concentration of naproxen reaching a gut mucosal cell depends both upon the drug's concentration in the lumen of the gut and the plasma concentration of the drug in mucosal capillaries.
It is generally believed that the mucus barrier in patients susceptible to gastrointestinal contact intolerance is somewhat deficient. Naproxen penetrates this barrier, inhibits the formation of the prostaglandins that sustain the mucus barrier and thereby allows hydrogen ions from the gastric lumen to penetrate and damage the mucosa.
This phenomenon leads to a need for a drug formulation that would avoid the problems of dispersion and topical contact with the gastric and upper duodenal mucosa. In principle, these problems can be avoided by using an "enteric" coating, i.e. one that is stable at low pH and dissolves at a higher pH (defined in Remington's Pharmaceutical Science, 18th Ed., pages 1669-1679).
One solution to the problems caused by solid controlled-release dosage forms is to use liquid-suspension controlled-release formulations. To be effective, they must be particularly homogeneous, suspendable and palatable as well in a form that guarantees the required release profile, and must therefore be made up of particles of sizes and characteristics that will allow the above requirements to be met.
Generally, the requirement for such small dimensions means keeping the excipient quantity ratio low in order to preserve the ability of the formulation to remain in suspension and to avoid a "sand-like" sensation upon ingestion. It is also particularly important to maintain a high concentration of active ingredient in the microgranules when treatment conditions require a high dosage, as is the case with naproxen.
For instance, in the formulations described in the international patent application WO 89/8448, the enteric-coated granules have diameters larger than 0.5 mm and, therefore, are totally unsuitable for suspension in liquid formulations.
Examples of formulations dimensionally suitable for liquid suspension for the administration of naproxen are described in the Belgian patent BE 903,540, which claims a powder controlled-release composition consisting of particles of sizes ranging from 0.1 to 125 .mu.m that are said to be suitable for the liquid administration of several drugs, including naproxen.
Copending commonly assigned U.S. patent application Ser. No. 928,616 (corresponding to EP 359,195) also describes a therapeutic system for liquid controlled-release-pharmaceutical compositions that can be used to administer naproxen. This system consists of microgranules coated first with a pH-insensitive (inner most) coating that imparts controlled release properties to the microgranules, followed by various alternate coats of lipophilic and hydrophilic materials so that the total size of the microgranules ranges from 50 to 500 .mu.m. The microgranules form stable suspensions in liquid administration vehicles.
However, by applying the teachings of the foregoing third party patents and applications, no liquid suspension naproxen-containing formulations have been developed that are capable of achieving therapeutically effective naproxen levels by a single daily administration. Furthermore, none of the liquid formulations described in the above patent applications is designed to get through the gastric fluid barrier. In addition, the foregoing copending U.S. patent application Ser. No. 928,616 does not specifically disclose a liquid controlled release formulation for naproxen suitable for a once-a-day administration nor a naproxen containing liquid formulation capable of withstanding gastric fluid.
It is thus an object of the present invention to provide a controlled-release pharmaceutical dosage form in liquid suspension delivering therapeutic levels of naproxen in the blood stream of a patent with a single daily administration, while avoiding the detrimental effects of prolonged contact of naproxen with the gastric mucous membrane.